Abstract
Cigarette smoking (CS) and genetic susceptibility determine the risk for development, progression, and severity of chronic obstructive pulmonary diseases (COPD). We posited that an incidental balanced reciprocal chromosomal translocation was linked to a patient's risk of severe COPD. We determined that 46,XX,t(1;4)(p13.1;q34.3) caused a breakpoint in the immunoglobulin superfamily member 3 (IGSF3) gene, with markedly decreased expression. Examination of COPDGene cohort identified 14 IGSF3 SNPs, of which rs1414272 and rs12066192 were directly and rs6703791 inversely associated with COPD severity, including COPD exacerbations. We confirmed that IGSF3 is a tetraspanin-interacting protein that colocalized with CD9 and integrin B1 in tetraspanin-enriched domains. IGSF3-deficient patient-derived lymphoblastoids exhibited multiple alterations in gene expression, especially in the unfolded protein response and ceramide pathways. IGSF3-deficient lymphoblastoids had high ceramide and sphingosine-1 phosphate but low glycosphingolipids and ganglioside levels, and they were less apoptotic and more adherent, with marked changes in multiple TNFRSF molecules. Similarly, IGSF3 knockdown increased ceramide in lung structural cells, rendering them more adherent, with impaired wound repair and weakened barrier function. These findings suggest that, by maintaining sphingolipid and membrane receptor homeostasis, IGSF3 is required for cell mobility-mediated lung injury repair. IGSF3 deficiency may increase susceptibility to CS-induced lung injury in COPD.
Highlights
Chronic obstructive pulmonary diseases (COPD), including emphysema, are a major cause of death worldwide
We identify a loss of immunoglobulin superfamily member 3 (IGSF3) expression due to germline mutation in a patient with severe emphysema, and we define the role of IGSF3 in lung cells and show that loss of IGSF3 affects cell’s sphingolipid metabolism, survival, adhesion, and wound injury repair — processes that might increase the susceptibility to cigarette smoking (CS)-induced lung injury
Using quantitative PCR targeted array and immunoblotting, we found that IGSF3 mRNA and protein were greatly reduced in the patient’s cells when compared with lymphoblastoid control cell lines (Figure 1, H and I)
Summary
Chronic obstructive pulmonary diseases (COPD), including emphysema, are a major cause of death worldwide. The most common risk factor for COPD is cigarette smoking (CS), only 30% of smokers are diagnosed with COPD, usually after the age of 50, indicating a significant genetic component for disease susceptibility. Following the discovery that homozygosity for Glu to Lys point mutation in SERPINA1, encoding for α-1 antitrypsin, is a genetic risk factor for COPD, there has been a keen interest in identifying other genes for COPD susceptibility. We set out to investigate if a stable balanced chromosomal translocation in a patient with manifestations of severe emphysema at a relatively young age caused a genetic disruption that increases the susceptibility of lung cells to injury. We hypothesized that the 46,XX,t(1;4)(p13.1;q34.3) translocation present in our patient might have caused disruption of immunoglobulin superfamily member 3 (IGSF3) on chromosome 1.
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